Neonatal anemia is the most commonly encountered hematologic problem among all neonates cared for in the neonatal intensive care unit (NICU). Project 1 seeks to better understand the pathophysiology and treatment of this challenging and important condition, especially as it affects premature, critically ill very low birth weight (VLBW) infants who require intensive laboratory blood monitoring leading to the need for multiple red blood cell (RBC) transfusions (RBCTX). In the revised research strategy proposed in Aims 1, 2 and 3, recombinant human erythropoietin (Epo) will first be administered to 1.0 to 1.5 kg VLBW infants; then comprehensive pharmacokinetics (PK) and pharmacodynamics (PD) data will be systematically gathered and analyzed to identify clinical and laboratory covariate parameters differentiating the infants based on their level of Epo responsiveness. Finally the Epo responsiveness predictors thus determined will be applied prospectively in the Aim 4 Study, a 2 x 2 design in which VLBW infants will be identified as good or poor EPO responders, based on the predictors, and then randomly assigned to receive Epo treatment or no treatment. This will test the central hvpothesis of Project 1: RBCTX can be eliminated in the majority of good Epo responders by optimal administration of Epo, but only marginal reductions in RBCTx will occur in the poor Epo responders. Project 1 challenges the prevailing thinking that the efficacy of Epo dosing in stimulating erythropoiesis is insufficient to eliminate the need for RBC transfusions in VLBW infants. Based on extensive preclinical and clinical PK/PD studies by our PPG team, we contend that previous Epo treatment studies in VLBW infants were not able to realize the full potential of Epo to eliminate RBCTX (in contrast to the very successful use of Epo in adult renal failure patients) because previous VLBW studies were conducted 1) without Epo dosing individualized for the complexities of neonatal erythropoiesis and PK/PD of Epo and 2) without consistent criteria for RBC transfusion, Epo dosing, and patient enrollment. The overall impact of Project 1 will be significant and potentially transformative: the development of a personalized, mechanism-driven approach built on sound principles will improve understanding of neonatal anemia and will be applicable to the care of premature, anemic infants. Project 1 synergizes with other PPG groups by expanding knowledge: 1) of erythropoiesis and Epo's PD (Projects 3 and 4); and 2) of PK and PD modeling (thromobopoiesis in Project 2).